We propose to study the factor(s) controlling the turnover of vascular endothelial cells. While the rate of turnover depends on the respective rates of cell death and cell proliferation, we will concentrate our efforts on the factor(s) that promote proliferation. Such factors are obviously necessary for repair following damage to the endothelium. We hope to determine how deficient or excessive proliferation of endothelial cells may be involved in the pathogenesis of vascular disease. First, we will determine what factors affect the proliferation of vascular endothelial cells in vitro. Since we have Fibroblast Growth Factor (FGF), the only purified mitogen for endothelial cells, we will study the effect of various agents (particularly those suspected of influencing vascular disease) on the potentiation or attenuation of the mitogenic effect of FGF. We will also compare the effect of FGF to that of other mitogens, such as those present in platelets. Second, we will use our knowledge of in vitro effects to determine how that factors control endothelial cell proliferation in vivo. Third, we will apply our knowledge of factors that affect endothelial cell proliferation to determine how such factors can influence the development of vascular diseases, particularly atherosclerosis. There are two major questions to be answered in the initial phase of the study: (1) Can inhibition of endothelial repair (by agents that inhibit endothelia cell proliferation) results in damage to the smooth muscle of the media leading to migration and proliferation of smooth muscle cells in the intima, thus forming an atherosclerotic plaque? (2) Can uncontrolled proliferation of endothelial cells lead by itself, to the development of an atherosclerotic plaque?